1. Field of the Invention
The present invention relates to a method for manufacturing an isoxazole derivative or a dihydroisoxazole derivative, and more particularly relates to a novel method for manufacturing an isoxazole derivative or a dihydroisoxazole derivative in which iron(III) nitrate is utilized, which results in a higher yield and no waste being discharged, and to novel isoxazole derivatives obtained by the manufacturing method.
2. Description of Related Art
Isoxazole derivatives are known to be compounds that have various pharmacological actions, such as anticancer action, anti-inflammatory action, and immunomodulatory action. Meanwhile, an isoxazole ring, which is a heterocycle, is a reaction intermediate that is useful in the pharmaceutical field and in organic synthesis because it can be converted by reductive ring cleavage into α, β unsaturated ketone, β-diketone, β-hydroxyketone, and γ-amylalcohol. In view of this, it would likely be extremely significant if a method could be developed for more efficiently synthesizing these isoxazole derivatives.
Up to now the construction of these heterocycles relied upon a method that went from a ketone compound through an oxime to a nitrile oxide, and involved 1,3-cycloaddition.
It is also known that when cerium(IV) ammonium nitrate (commonly referred to as CAN(IV)) is allowed to act on an alkene or an alkyne, which are compounds having carbon-carbon unsaturated double or triple bonds, at 80° C. in acetophenone or under reflux in acetone, this results in the nitration of the solvent molecules and the production of nitrile oxide, and then a 1,3-dipolar cycloaddition reaction gives an isoxazole derivative at a high yield and in a single step, and that when nitric acid and CAN(III) are used instead of CAN(IV), the same reaction occurs, fewer by-products are produced, and the yield is even higher (see, for example, K. Itoh, S. Takahashi, T. Ueki, T. Takahashi, and C. A. Horiuchi, Tetrahedron Letters, 43 (2002), pp. 7035-7037, and K. Itoh and C. A. Horiuchi, Tetrahedron, 60 (2004), pp. 1671-1681).